title: Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway.
abstract: All bactericidal antibiotics were recently proposed to kill by inducing reactive oxygen species (ROS) production, causing destabilization of iron-sulfur (Fe-S) clusters and generating Fenton chemistry. We find that the ROS response is dispensable upon treatment with bactericidal antibiotics. Furthermore, we demonstrate that Fe-S clusters are required for killing only by aminoglycosides. In contrast to cells, using the major Fe-S cluster biosynthesis machinery, ISC, cells using the alternative machinery, SUF, cannot efficiently mature respiratory complexes I and II, resulting in impendence of the proton motive force (PMF), which is required for bactericidal aminoglycoside uptake. Similarly, during iron limitation, cells become intrinsically resistant to aminoglycosides by switching from ISC to SUF and down-regulating both respiratory complexes. We conclude that Fe-S proteins promote aminoglycoside killing by enabling their uptake.
authors.affiliation: Laboratoire de Chimie Bactérienne, Aix-Marseille Université, CNRS, UMR 7283, Institut de Microbiologie de la Méditerranée, 31 Chemin Joseph Aiguier, 13009 Marseille France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ezraty
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vergnes
authors.forename: Manuel
authors.initials: M
authors.lastname: Banzhaf
authors.forename: Yohann
authors.initials: Y
authors.lastname: Duverger
authors.forename: Allison
authors.initials: A
authors.lastname: Huguenot
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Brochado
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Su
authors.forename: Leon
authors.initials: L
authors.lastname: Espinosa
authors.forename: Laurent
authors.initials: L
authors.lastname: Loiseau
authors.forename: Béatrice
authors.initials: B
authors.lastname: Py
authors.forename: Athanasios
authors.initials: A
authors.lastname: Typas
authors.forename: Frédéric
authors.initials: F
authors.lastname: Barras
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism* / Q000494:pharmacology*; D000667:Ampicillin / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D005839:Gentamicins / Q000378:metabolism / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; D005839:Gentamicins; D007506:Iron-Sulfur Proteins; C487901:IscA protein, E coli; C411665:IscU protein, E coli; D017382:Reactive Oxygen Species; C503794:Suf E protein, E coli; D000667:Ampicillin; D007501:Iron; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I